Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study

Background In the UK, women are invited for 3-yearly mammography screening, through the NHS Breast Screening Programme (NHSBSP), from the ages of 47–50 years to the ages of 69–73 years. Women with family histories of breast cancer can, from the age of 40 years, obtain enhanced surveillance and, in exceptionally high-risk cases, magnetic resonance imaging. However, no NHSBSP risk assessment is undertaken. Risk prediction models are able to categorise women by risk using known risk factors, although accurate individual risk prediction remains elusive. The identification of mammographic breast density (MD) and common genetic risk variants [single nucleotide polymorphisms (SNPs)] has presaged the improved precision of risk models. Objectives To (1) identify the best performing model to assess breast cancer risk in family history clinic (FHC) and population settings; (2) use information from MD/SNPs to improve risk prediction; (3) assess the acceptability and feasibility of offering risk assessment in the NHSBSP; and (4) identify the incremental costs and benefits of risk stratified screening in a preliminary cost-effectiveness analysis. Design Two cohort studies assessing breast cancer incidence. Setting High-risk FHC and the NHSBSP Greater Manchester, UK. Participants A total of 10,000 women aged 20–79 years [Family History Risk Study (FH-Risk); UK Clinical Research Network identification number (UKCRN-ID) 8611] and 53,000 women from the NHSBSP [aged 46–73 years; Predicting the Risk of Cancer At Screening (PROCAS) study; UKCRN-ID 8080]. Interventions Questionnaires collected standard risk information, and mammograms were assessed for breast density by a number of techniques. All FH-Risk and 10,000 PROCAS participants participated in deoxyribonucleic acid (DNA) studies. The risk prediction models Manual method, Tyrer–Cuzick (TC), BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) and Gail were used to assess risk, with modelling based on MD and SNPs. A preliminary model-based cost-effectiveness analysis of risk stratified screening was conducted. Main outcome measures Breast cancer incidence. Data sources The NHSBSP; cancer registration. Results A total of 446 women developed incident breast cancers in FH-Risk in 97,958 years of follow-up. All risk models accurately stratified women into risk categories. TC had better risk precision than Gail, and BOADICEA accurately predicted risk in the 6268 single probands. The Manual model was also accurate in the whole cohort. In PROCAS, TC had better risk precision than Gail [area under the curve (AUC) 0.58 vs. 0.54], identifying 547 prospective breast cancers. The addition of SNPs in the FH-Risk case–control study improved risk precision but was not useful in BRCA1 (breast cancer 1 gene) families. Risk modelling of SNPs in PROCAS showed an incremental improvement from using SNP18 used in PROCAS to SNP67. MD measured by visual assessment score provided better risk stratification than automatic measures, despite wide intra- and inter-reader variability. Using a MD-adjusted TC model in PROCAS improved risk stratification (AUC = 0.6) and identified significantly higher rates (4.7 per 10,000 vs. 1.3 per 10,000; p < 0.001) of high-stage cancers in women with above-average breast cancer risks. It is not possible to provide estimates of the incremental costs and benefits of risk stratified screening because of lack of data inputs for key parameters in the model-based cost-effectiveness analysis. Conclusions Risk precision can be improved by using DNA and MD, and can potentially be used to stratify NHSBSP screening. It may also identify those at greater risk of high-stage cancers for enhanced screening. The cost-effectiveness of risk stratified screening is currently associated with extensive uncertainty. Additional research is needed to identify data needed for key inputs into model-based cost-effectiveness analyses to identify the impact on health-care resource use and patient benefits. Future work A pilot of real-time NHSBSP risk prediction to identify women for chemoprevention and enhanced screening is required. Funding The National Institute for Health Research Programme Grants for Applied Research programme. The DNA saliva collection for SNP analysis for PROCAS was funded by the Genesis Breast Cancer Prevention Appeal.